Genetic Variant TRAF3:p.Ser503Ser (chr14-102905586-C-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_145725.3(TRAF3):c.1509C>T(p.Ser503Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,614,156 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0030 ( 16 hom. )

Consequence

TRAF3
NM_145725.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.480

Publications

2 publications found

Variant links:

Genes affected

TRAF3 (HGNC:12033): (TNF receptor associated factor 3) The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins associate with, and mediate the signal transduction from, members of the TNF receptor (TNFR) superfamily. This protein participates in the signal transduction of CD40, a TNFR family member important for the activation of the immune response. This protein is found to be a critical component of the lymphotoxin-beta receptor (LTbetaR) signaling complex, which induces NF-kappaB activation and cell death initiated by LTbeta ligation. Epstein-Barr virus encoded latent infection membrane protein-1 (LMP1) can interact with this and several other members of the TRAF family, which may be essential for the oncogenic effects of LMP1. The protein also plays a role in the regulation of antiviral response. Mutations in this are associated with Encephalopathy, acute, infection-induced, herpes-specific 5. [provided by RefSeq, Jul 2020]

TRAF3 Gene-Disease associations (from GenCC):

herpes simplex encephalitis, susceptibility to, 3
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
TRAF3 haploinsufficiency
Inheritance: AD Classification: MODERATE Submitted by: ClinGen

TRAF3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 14-102905586-C-T is Benign according to our data. Variant chr14-102905586-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 540501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.48 with no splicing effect.

BS2

High AC in GnomAd4 at 410 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145725.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRAF3	NM_145725.3	MANE Select	c.1509C>T	p.Ser503Ser	synonymous	Exon 12 of 12	NP_663777.1	Q13114-1
TRAF3	NM_003300.4		c.1509C>T	p.Ser503Ser	synonymous	Exon 11 of 11	NP_003291.2
TRAF3	NM_145726.3		c.1434C>T	p.Ser478Ser	synonymous	Exon 11 of 11	NP_663778.1	A6NHG8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRAF3	ENST00000392745.8	TSL:1 MANE Select	c.1509C>T	p.Ser503Ser	synonymous	Exon 12 of 12	ENSP00000376500.3	Q13114-1
TRAF3	ENST00000560371.5	TSL:1	c.1509C>T	p.Ser503Ser	synonymous	Exon 11 of 11	ENSP00000454207.1	Q13114-1
TRAF3	ENST00000351691.10	TSL:1	c.1434C>T	p.Ser478Ser	synonymous	Exon 11 of 11	ENSP00000332468.5	A6NHG8

Frequencies

GnomAD3 genomes

AF:

0.00270

AC:

411

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00307

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00260

AC:

655

AN:

251486

AF XY:

0.00270

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0100

Gnomad NFE exome

AF:

0.00304

Gnomad OTH exome

AF:

0.00309

GnomAD4 exome

AF:

0.00304

AC:

4437

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00299

AC XY:

2175

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33480

American (AMR)

AF:

0.00139

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000325

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00975

AC:

521

AN:

53418

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00329

AC:

3663

AN:

1112012

Other (OTH)

AF:

0.00235

AC:

142

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

311

621

932

1242

1553

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

272

408

544

680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00269

AC:

410

AN:

152264

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

219

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000698

AC:

AN:

41550

American (AMR)

AF:

0.00242

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0123

AC:

130

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00306

AC:

208

AN:

68020

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00229

Hom.:

Bravo

AF:

0.00188

EpiCase

AF:

0.00267

EpiControl

AF:

0.00196

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Herpes simplex encephalitis, susceptibility to, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

7.2

(source)

DANN

Benign

0.47

PhyloP100

-0.48

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over